CN114907377A - Condensed tetracyclic compound, its preparation method and its application in medicine - Google Patents

Abstract

The present disclosure relates to fused tetracyclic compounds, their preparation methods and their medical applications. Specifically, the present disclosure relates to a condensed tetracyclic compound represented by the general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and its use as a therapeutic agent, especially its use in the preparation of Use in drugs that inhibit HPK1. wherein each group in the general formula (I) is as defined in the specification.

Description

Condensed tetracyclic compound, its preparation method and its application in medicine

technical field

The present disclosure belongs to the field of medicine, and relates to a condensed tetracyclic compound, a preparation method thereof and its application in medicine. In particular, the present disclosure relates to a fused tetracyclic compound represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and its use in the preparation of a medicament for inhibiting HPK1.

Background technique

Anticancer therapy has entered the era of immunotherapy from chemoradiotherapy, targeted therapy, and immunotherapy. The targets of tumor immunotherapy mainly include immune checkpoints, immune agonists, Treg, macrophages, tumor microenvironment metabolites such as IDO, A2AR pathway, and so on. Hematopoietic Progenitor Kinase 1 (HPK1 for short; also known as mitogen-activated protein kinase kinase kinase 1 or Mitogen-activated protein kinase kinase kinase 1, referred to as MAP4K1) is a negative regulator in T cells, which is activated in TCR. Later, the function of negative feedback regulation is related to T cell exhaustion. The well-studied signaling pathway is: after TCR binds to MHC-peptide, LAT is phosphorylated, recruiting the GADS-SLP76 complex, causing the phosphorylation of downstream PLC and activation of the pathway. At the same time, ZAP70 phosphorylates the Y381 site of HPK1, which binds to the SH2 region of SLP76, thereby phosphorylating the latter's S376 site. SLP76 S376 phosphorylation recruits 14-3-3, which leads to ubiquitination and disassembly of the entire TCR signalosome.

At present, HPK1 is considered to be a good immunotherapy target for the following three reasons: (1) HPK1 expression profile is limited to immune cells, and it is safe; (2) HPK1 has multiple functions in different stages of the "cancer-immune cycle". Inhibition of HPK1 can regulate the immunosuppressive function of NK cells, DC cells, and T cells, and can also regulate the activation of B cells, among which T cell activation is the most studied; (3) HPK1 kinase activity is involved in inhibiting anti-cancer immune responses. important in.

Studies have shown that HPK1 expression is associated with T cell exhaustion signatures, including CD3E, PD1, CTLA4, TIM-3, LAG-3 and TIGIT, and high HPK1 expression is associated with shorter survival. TCGA PanCancer database analysis showed a positive correlation between HPK1 (but not other MAP4K family members) expression and PD1. The expression of HPK1 was up-regulated in exhausted T cells, and the expression of HPK1, TIM3 and LAG3 was higher in PD1-high T cells than in PD1-low T cells. In contrast, HPK1 was down-regulated in CD4+ T cells from patients with systemic lupus erythematosus (SLE), and SLEDAI scores were negatively correlated with HPK1 mRNA levels. The expression of HPK1 was also down-regulated in peripheral blood cells of patients with psoriatic arthritis (PsA).

The HPK1 knockout mice did not have any abnormality in the resting state. Once the TCR is activated, whether it is HPK1 knockout, HPK1 kinase dead knock-in, or SLP76S376A knock-in mice, the results are similar, and the immune response will be activated. HPK1-deficient mice are more susceptible to experimental autoimmune encephalomyelitis (EAE). HPK1 kinase activity modulates TCR signaling and cytokine secretion in vitro; inhibition of HPK1 alleviates PGE2- and adenosine-mediated immunosuppression. HPK1kinase dead mice inhibited tumor growth in vivo, and after depletion of CD8+ or CD4+ T cells, the antitumor effect of HPK1-/- mice almost disappeared, indicating that T cells mediate most of the immunosuppressive effects of HPK1.

The above mouse data of HPK1 knockout and kinase dead knock-in show that HPK1 mainly acts through kinase activity, but some literatures report that its scaffold also has certain functions, so the idea of drug development to inhibit HPK1 is mainly kinase inhibitors. There are also some PROTAC molecules.

The related patents disclosed so far include WO2016205942A1, WO2019238067A1, WO2021013083A1 and WO2021000925A1 and so on.

SUMMARY OF THE INVENTION

The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof:

in:

Ring A is selected from aryl, heterocyclyl and heteroaryl;

T ¹ is CR ^T1 or nitrogen atom;

G ³ and G ⁴ are the same or different, and are each independently CR ¹ or a nitrogen atom;

^G8 is CR ^G8 or nitrogen atom;

G ¹ and G ² are the same or different, and are each independently selected from CR ² , NR ³ , a nitrogen atom, an oxygen atom, and a sulfur atom;

G ⁵ and G ⁶ are the same or different, and are each independently selected from CR ⁴ R ⁵ , NR ⁶ , an oxygen atom and a sulfur atom;

^G7 is selected from CR ^G7a R ^G7b , NR ^G7c , oxygen atom and sulfur atom;

^{G9 is} selected from CR ^G9a R ^G9b , NR ^G9c , oxygen atom and sulfur atom;

R is the same or different, and is each independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, and hydroxyalkyl; or

Two Rs together form an oxo group;

R ⁰ , R ³ , R ⁶ , R ^G7c and R ^G9c are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group , aryl and heteroaryl;

R', R ¹ , R ^T1 , R ^G8 and R ² are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano group, amino, -(CH ₂ ) _m NR ⁷ R ⁸ , -OR ⁹ , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, Alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, Substituted with one or more substituents of haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁴ , R ⁵ , R ^G7a , R ^G7b , R ^G9a and R ^G9b are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy group, cyano group, amino group, nitro group, hydroxyl group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, wherein said alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkane group group, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, substituted with one or more substituents of hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; or

One pair of R ⁴ and R ⁵ , R ^G7a and R ^G7b or R ^G9a and R ^{G9b together} form an oxo group;

R ⁷ and R ⁸ are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; or

R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a heterocyclyl group optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, Substitution of one or more of amino, nitro, hydroxy and hydroxyalkyl groups;

R ⁹ is selected from hydrogen atom, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group;

m is 0, 1, 2, 3 or 4;

q is 0, 1, 2, 3 or 4; and

n is 0, 1, 2, 3, 4, 5 or 6.

Another aspect of the present disclosure relates to a compound represented by the general formula (I-1) or (I-2) or a pharmaceutically acceptable salt thereof:

wherein rings A, T ¹ , G ¹ to G ⁹ , R′, R ⁰ , R, q and n are as defined in general formula (I).

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof,

为

T³为CR^T3或氮原子，T⁵、T⁶和T⁷相同或不同，且各自独立地为CR¹⁰或氮原子；in

for

T ³ is CR ^T3 or a nitrogen atom, T ⁵ , T ⁶ and T ⁷ are the same or different, and are each independently CR ¹⁰ or a nitrogen atom;

T ² and T ⁴ are the same or different, and are each independently selected from CR ¹¹ , NR ¹² , a nitrogen atom, an oxygen atom, and a sulfur atom;

R ¹⁰ , R ^T3 and R ¹¹ are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -( CH ₂ ) _m NR ⁷ R ⁸ , -OR ⁹ , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, Alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano , substituted with one or more substituents in amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ¹² is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

R ⁷ , R ⁸ , R ⁹ and m are as defined in general formula (I), (I-1) or (I-2).

为

R¹⁰、R^T3和R¹¹相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、-(CH₂)_mNR⁷R⁸、-OR⁹、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein

for

R ¹⁰ , R ^T3 and R ¹¹ are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -( CH ₂ ) _m NR ⁷ R ⁸ , -OR ⁹ , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, Alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano , substituted with one or more substituents in amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁷ , R ⁸ , R ⁹ and m are as defined in general formula (I), (I-1) or (I-2).

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from 5-6 Membered heteroaryl, 5-6 membered heterocyclyl and phenyl.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein R ⁰ is selected from a hydrogen atom, C _1-6 alkyl and C _1-6 haloalkyl; preferably, R ⁰ is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein G ¹ is a nitrogen atom.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein G ² is NH.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein ^G7 is CR ^G7a R ^G7b , R ^G7a and R ^G7b are as defined in general formula (I), (I-1) or (I-2); preferably, G ⁷ is CH ₂ .

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein G ⁸ is a nitrogen atom.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein T ² is CR ¹¹ , R ¹¹ is as defined in general formula (I), (I-1) or (I-2); preferably, R ¹¹ is selected from hydrogen atom, halogen and C _1-6 alkyl; more preferably, T ² is CH .

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein T ³ is CR ^T3 , R ^T3 is as defined in general formula (I), (I-1) or (I-2); preferably, R ^T3 is selected from hydrogen atom, halogen and C _1-6 alkyl; more preferably, T ³ is CH .

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein T ⁴ is an oxygen atom or sulfur atom ^; preferably, T4 is a sulfur atom.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein T ⁵ is CR ¹⁰ , R ¹⁰ is as defined in general formula (I), (I-1) or (I-2); preferably, R ¹⁰ is selected from hydrogen atom, halogen and C _1-6 alkyl; further preferably, T ⁵ is CR ¹⁰ , R ¹⁰ is a hydrogen atom or halogen; more preferably, T ⁵ is CH or CF; most preferably, T ⁵ is CH.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein T ⁶ is CR ¹⁰ , R ¹⁰ is as defined in general formula (I), (I-1) or (I-2); preferably, R ¹⁰ is selected from hydrogen atom, halogen and C _1-6 alkyl; more preferably, T ⁶ is CH .

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein T ⁷ is CR ¹⁰ , R ¹⁰ is as defined in general formula (I), (I-1) or (I-2); preferably, R ¹⁰ is selected from hydrogen atom, halogen and C _1-6 alkyl; more preferably, T ⁷ is CH .

Another aspect of the present disclosure relates to a compound represented by general formula (II) or (III) or a pharmaceutically acceptable salt thereof:

in:

T ¹ , G ³ , G ⁴ , G ⁵ , G ⁶ , G ⁹ , R, R′, q and n are as defined in general formula (I).

The present disclosure also relates to a compound represented by the general formula (II-1), (II-2), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof:

T ¹ , G ³ , G ⁴ , G ⁵ , G ⁶ , G ⁹ , R, R′, q and n are as defined in general formula (I).

In some preferred embodiments of the present disclosure, the general formulae (I), (I-1), (I-2), (II), (II-1), (II-2), (III) , the compound shown in (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein G ⁵ is CR ⁴ R ⁵ or oxygen atom; and/or G ⁶ is CR ⁴ R ⁵ or oxygen atom; Preferably, one of G ⁵ and G ⁶ is CR ⁴ R ⁵ , and the other is an oxygen atom; R ⁴ and R ⁵ are as shown in general formula (I), (I-1), (I-2), (II), (II-1), (II-2), (III), (III-1) or (III-2); more preferably, one of G ⁵ and G ⁶ is CH ₂ and the other is oxygen atom ^; most preferably, G5 is an oxygen atom and ^G6 is _CH2 .

In some preferred embodiments of the present disclosure, the general formulae (I), (I-1), (I-2), (II), (II-1), (II-2), (III) , (III-1) or a compound shown in (III-2) or a pharmaceutically acceptable salt thereof, wherein G ⁹ is NR ^G9c , and R ^G9c is a hydrogen atom or a C _1-6 alkyl group; preferably, G ⁹ is NCH ₃ or NH; more preferably, G ⁹ is NCH ₃ .

In some preferred embodiments of the present disclosure, the general formulae (I), (I-1), (I-2), (II), (II-1), (II-2), (III) , a compound represented by (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein G ⁹ is an oxygen atom.

In some preferred embodiments of the present disclosure, the general formulae (I), (I-1), (I-2), (II), (II-1), (II-2), (III) , (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein G ³ is CR ¹ ; and/or G ⁴ is CR ¹ ; R ¹ is as shown in general formula (I), ( As defined in I-1), (I-2), (II), (II-1), (II-2), (III), (III-1) or (III-2); preferably, R ¹ is selected from hydrogen atom, halogen and _C1-6 alkyl; more preferably, G3 is CH ^; and/or ^G4 is CH.

In some preferred embodiments of the present disclosure, the general formulae (I), (I-1), (I-2), (II), (II-1), (II-2), (III) , (III-1) or the compound shown in (III-2) or a pharmaceutically acceptable salt thereof, wherein T ¹ is CR ^T1 ; R ^T1 is such as general formula (I), (I-1), (I-2 ), (II), (II-1), (II-2), (III), (III-1) or (III-2); preferably, R ^T1 is selected from hydrogen atom, halogen, C _1-6 alkyl, amino, cyano, hydroxy, C _1-6 hydroxyalkyl and -CH ₂ -NH ₂ ; more preferably, T ¹ is C-NH ₂ .

In some preferred embodiments of the present disclosure, the general formulae (I), (I-1), (I-2), (II), (II-1), (II-2), (III) , the compound shown in (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein R is the same or different, and each is independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _{1 -6} alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, amino, hydroxyl and C _1-6 hydroxyalkyl; or two Rs taken together to form oxo; preferably, R The same or different, and each is independently selected from a hydrogen atom, a halogen and a C _1-6 alkyl group; more preferably, R is a hydrogen atom.

In some preferred embodiments of the present disclosure, the general formulae (I), (I-1), (I-2), (II), (II-1), (II-2), (III) , the compound shown in (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein R' is the same or different, and each is independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, amino, hydroxyl and C _1-6 hydroxyalkyl; preferably, R' is the same or different, and each independently Selected from hydrogen atom, halogen and C _1-6 alkyl; more preferably, R' is hydrogen atom or halogen.

In some preferred embodiments of the present disclosure, the general formulae (I), (I-1), (I-2), (II), (II-1), (II-2), (III) , the compound represented by (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2; preferably, m is 0 or 1.

In some preferred embodiments of the present disclosure, the general formulae (I), (I-1), (I-2), (II), (II-1), (II-2), (III) , a compound represented by (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2.

In some preferred embodiments of the present disclosure, the general formulae (I), (I-1), (I-2), (II), (II-1), (II-2), (III) , the compound represented by (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein q is 0, 1 or 2; preferably, q is 0 or 1.

In some preferred embodiments of the present disclosure, the general formulae (I), (I-1), (I-2), (II), (II-1), (II-2), (III) , the compound represented by (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2; preferably, n is 0 or 1.

In some preferred embodiments of the present disclosure, the general formulae (I), (I-1), (I-2), (II), (II-1), (II-2), (III) , (III-1) or a compound shown in (III-2) or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, amino, -(CH ₂ ) _m NR ⁷ R ⁸ , hydroxy and C _1-6 hydroxyalkyl, m is 1 or 2, R ⁷ and R ⁸ are the same or different, and are each independently a hydrogen atom or a C _1-6 alkyl group; preferably, R ¹ is selected from hydrogen atom, halogen, C _1-6 alkyl group, amino group, cyano group, hydroxyl group, C _1-6 Hydroxyalkyl and -CH ₂ -NH ₂ ; more preferably, R ¹ is selected from hydrogen atoms, halogens and C _1-6 alkyl groups; most preferably, R ¹ is a hydrogen atom.

In some preferred embodiments of the present disclosure, the general formulae (I), (I-1), (I-2), (II), (II-1), (II-2), (III) , (III-1) or the compound shown in (III-2) or a pharmaceutically acceptable salt thereof, wherein R ^T1 is selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, amino, -(CH ₂ ) _m NR ⁷ R ⁸ , hydroxy and C _1-6 hydroxyalkyl, m is 1 or 2, R ⁷ and R ⁸ are the same or different, and are each independently a hydrogen atom or a C _1-6 alkyl group; preferably, R ^T1 is selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, an amino group, a cyano group, a hydroxyl group, a C _1-6 group Hydroxyalkyl and _-CH2 - _NH2 ; more preferably, R ^T1 is amino.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein R ^G8 is selected from a hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, amino, -(CH ₂ ) _m NR ⁷ R ⁸ , hydroxy and C _1-6 hydroxyalkyl group, m is 1 or 2, R ⁷ and R ⁸ are the same or different, and each is independently a hydrogen atom or a C _1-6 alkyl group; preferably, R ^G8 is selected from hydrogen atom, halogen, C _1-6 alkyl, amino, cyano, hydroxyl, C _1-6 hydroxyalkyl and -CH ₂ -NH ₂ ; more preferably, R ^G8 is selected from hydrogen atom, halogen and C _1-6 alkyl.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein R ² is selected from a hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, amino, -(CH ₂ ) _m NR ⁷ R ⁸ , hydroxy and C _1-6 hydroxyalkyl group, m is 1 or 2, R ⁷ and R ⁸ are the same or different, and each is independently a hydrogen atom or a C _1-6 alkyl group; preferably, R ² is selected from hydrogen atom, halogen and C _1-6 alkyl.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein R ³ is selected from a hydrogen atom, C _1-6 alkyl and C _1-6 haloalkyl; preferably, R ³ is a hydrogen atom.

In some preferred embodiments of the present disclosure, the general formulae (I), (I-1), (I-2), (II), (II-1), (II-2), (III) , the compound shown in (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein R ⁴ and R ⁵ are the same or different, and are independently selected from hydrogen atom, halogen, C _1-6 alkane group, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, amino, hydroxyl and C _1-6 hydroxyalkyl, or R ⁴ and R ⁵ together form oxo group; preferably, R ⁴ and R ⁵ are the same or different, and are each independently selected from hydrogen atoms, halogens, and C _1-6 alkyl groups; more preferably, R ⁴ and R ⁵ are hydrogen atoms.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein R ^G7a and R ^G7b are the same or different, and each is independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, amino, hydroxyl and C _1-6 hydroxyalkyl, or R ^G7a and R ^G7b together form an oxo group; preferably, R ^G7a and R ^G7b are the same or different, and are each independently selected from hydrogen, halogen and C _1-6 alkyl; More preferably, R ^G7a and R ^G7b are hydrogen atoms.

In some preferred embodiments of the present disclosure, the general formulae (I), (I-1), (I-2), (II), (II-1), (II-2), (III) , the compound shown in (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein R ^G9a and R ^G9b are the same or different, and are independently selected from hydrogen atom, halogen, C _1-6 alkane group, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, amino, hydroxyl and C _1-6 hydroxyalkyl, or R ^G9a and R ^G9b together form oxo group; preferably, R ^G9a and R ^G9b are the same or different, and are each independently selected from a hydrogen atom, a halogen and a C _1-6 alkyl group.

In some preferred embodiments of the present disclosure, the general formulae (I), (I-1), (I-2), (II), (II-1), (II-2), (III) , the compound shown in (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein R ⁶ is selected from a hydrogen atom, a C _1-6 alkyl group and a C _1-6 haloalkyl group; preferably, R ⁶ is a hydrogen atom or a C _1-6 alkyl group.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein R ^{G7c is} selected from a hydrogen atom, C _1-6 alkyl and C _1-6 haloalkyl; preferably, R ^G7c is a hydrogen atom or a C _1-6 alkyl.

In some preferred embodiments of the present disclosure, the general formulae (I), (I-1), (I-2), (II), (II-1), (II-2), (III) , (III-1) or a compound shown in (III-2) or a pharmaceutically acceptable salt thereof, wherein R ^{G9c is} selected from hydrogen atom, C _1-6 alkyl and C _1-6 haloalkyl; preferably, R ^G9c is a hydrogen atom or a C _1-6 alkyl group, more preferably a methyl group.

In some preferred embodiments of the present disclosure, the general formulae (I), (I-1), (I-2), (II), (II-1), (II-2), (III) , (III-1) or a compound shown in (III-2) or a pharmaceutically acceptable salt thereof, wherein R ⁷ and R ⁸ are the same or different, and are each independently a hydrogen atom or a C _1-6 alkyl group; preferably Typically, R ⁷ and R ⁸ are the same or different, and are each independently a hydrogen atom or a methyl group.

In some preferred embodiments of the present disclosure, the general formulae (I), (I-1), (I-2), (II), (II-1), (II-2), (III) , (III-1) or (III-2), or a pharmaceutically acceptable salt thereof, wherein R ⁹ is selected from a hydrogen atom, a C _1-6 alkyl group and a C _1-6 haloalkyl group.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is selected from a hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, amino, -(CH ₂ ) _m NR ⁷ R ⁸ , hydroxy and C _1-6 hydroxyalkyl group, m is 1 or 2, R ⁷ and R ⁸ are the same or different, and each is independently a hydrogen atom or a C _1-6 alkyl group; preferably, R ¹⁰ is selected from hydrogen atom, halogen, C _1-6 alkyl, amino, cyano, hydroxyl, C _1-6 hydroxyalkyl and -CH ₂ -NH ₂ ; further preferably, R ¹⁰ is selected from hydrogen atom, halogen and C _1-6 alkyl; more preferably Preferably, R ¹⁰ is a hydrogen atom or halogen.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein R ^T3 is selected from a hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, amino, -(CH ₂ ) _m NR ⁷ R ⁸ , hydroxy and C _1-6 hydroxyalkyl group, m is 1 or 2, R ⁷ and R ⁸ are the same or different, and each is independently a hydrogen atom or a C _1-6 alkyl group; preferably, R ^T3 is selected from hydrogen atom, halogen, C _1-6 alkyl, amino, cyano, hydroxyl, C _1-6 hydroxyalkyl and -CH ₂ -NH ₂ ; more preferably, R ^T3 is selected from hydrogen, halogen and C _1-6 alkyl; most preferably Preferably, R ^T3 is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is selected from a hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, amino, -(CH ₂ ) _m NR ⁷ R ⁸ , hydroxy and C _1-6 hydroxyalkyl group, m is 1 or 2, R ⁷ and R ⁸ are the same or different, and each is independently a hydrogen atom or a C _1-6 alkyl group; preferably, R ¹¹ is selected from hydrogen atom, halogen and C _1-6 alkyl; more preferably, R ¹¹ is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein R ¹² is selected from a hydrogen atom, C _1-6 alkyl and C _1-6 haloalkyl; preferably, R ¹² is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (II), (II-1), (II-2), (III), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein R' is selected from hydrogen atom, halogen and C _1-6 alkyl, q is 0 or 1, T ¹ is CR ^T1 , R ^T1 is selected from hydrogen atom, halogen, C _1-6 Alkyl, amino, cyano, hydroxy, C _1-6 hydroxyalkyl and -CH ₂ -NH ₂ , G ³ is CR ¹ , G ⁴ is CR ¹ , R ¹ is each independently selected from hydrogen, halogen and C _1-6 alkyl, one of G ⁵ and G ⁶ is CH ₂ , the other is an oxygen atom, G ⁹ is NR ^G9c , R ^G9c is hydrogen atom or C _1-6 alkyl, R is selected from hydrogen atom, halogen and C _1-6 alkyl, n is 0 or 1.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (II), (II-1), (II-2), (III), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein R' is hydrogen atom or halogen, q is 0 or 1, T ¹ is C-NH ₂ , G ³ is CH, G ⁴ is CH, G ⁵ is oxygen atom, G ⁶ is CH ₂ , G ⁹ are NR ^G9c , R ^G9c is a hydrogen atom or a C _1-6 alkyl group, and R is a hydrogen atom.

Table A Typical compounds of the present disclosure include, but are not limited to:

Another aspect of the present disclosure relates to a compound of formula (IA) or a salt thereof,

Wherein: R ^w is alkyl;

G ¹ to G ⁹ , R and n are as defined in general formula (I).

Another aspect of the present disclosure relates to a compound represented by general formula (I-1A) or (I-2A) or a salt thereof,

Wherein: R ^w is alkyl;

G ¹ to G ⁹ , R and n are as defined in general formula (I).

Another aspect of the present disclosure relates to a compound of general formula (IIA) or a salt thereof,

Wherein: R ^w is alkyl;

G ³ to G ⁶ , G ⁹ , R and n are as defined in general formula (II).

Another aspect of the present disclosure relates to a compound represented by general formula (II-1A) or (II-2A) or a salt thereof,

Wherein: R ^w is alkyl;

G ³ to G ⁶ , G ⁹ , R and n are as defined in general formula (II).

Another aspect of the present disclosure relates to a compound of general formula (IC) or a salt thereof,

Wherein: R ^m is amino protecting group; Preferably Boc;

Rings A, T ¹ , R′, R ⁰ , G ¹ to G ⁸ , R, q and n are as defined in general formula (I). Another aspect of the present disclosure relates to a compound of general formula (IIC) or (IIIC) or a salt thereof,

Wherein: R ^m is amino protecting group; Preferably Boc;

T ¹ , R′, G ³ to G ⁶ , R, q and n are as defined in general formula (II) or (III). Typical intermediate compounds of the present disclosure include, but are not limited to:

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (IA) or its salt is subjected to cyclization reaction with the compound of general formula (IB) or its salt to obtain the compound of general formula (I) or its pharmaceutically acceptable salt;

in:

R ^w is alkyl, preferably ethyl;

T ¹ is C-NH ₂ ;

Rings A, R ⁰ , R', q, G ¹ to G ⁹ , R and n are as defined in general formula (I).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (I) or a pharmaceutically acceptable salt thereof is resolved to obtain a compound represented by general formula (I-1) or (I-2) or a pharmaceutically acceptable salt thereof;

in:

Rings A, T ¹ , R ⁰ , R′, q, G ¹ to G ⁹ , R and n are as defined in general formula (I-1) or (I-2).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (I-1A) or its salt is subjected to cyclization reaction with the compound of general formula (IB) or its salt to obtain the compound of general formula (I-1) or its pharmaceutically acceptable salt; or

The compound of general formula (I-2A) or its salt is subjected to cyclization reaction with the compound of general formula (IB) or its salt to obtain the compound of general formula (I-2) or its pharmaceutically acceptable salt;

in:

R ^w is alkyl, preferably ethyl;

T ¹ is C-NH ₂ ;

Rings A, R ⁰ , R', q, G ¹ to G ⁹ , R and n are as defined in general formula (I-1) or (I-2).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (IIA) or its salt is subjected to cyclization reaction with the compound of general formula (IIB) or its salt to obtain the compound of general formula (II) or its pharmaceutically acceptable salt;

in:

R ^w is alkyl, preferably ethyl;

T ¹ is C-NH ₂ ;

G3, G4, ^G5 , ^G6 , ^G9 , ^R , R', q and n are as defined in general ^formula (II).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1) or (II-2) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (II) or a pharmaceutically acceptable salt thereof is obtained through resolution to obtain a compound of general formula (II-1) or (II-2) or a pharmaceutically acceptable salt thereof;

in:

T ¹ , G ³ , G ⁴ , G ⁵ , G ⁶ , G ⁹ , R, R′, q and n are as defined in general formula (II-1) or (II-2).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1) or (II-2) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (II-1A) or its salt is subjected to cyclization reaction with the compound of general formula (IIB) or its salt to obtain the compound of general formula (II-1) or its pharmaceutically acceptable salt; or

The compound of general formula (II-2A) or its salt is subjected to cyclization reaction with the compound of general formula (IIB) or its salt to obtain the compound of general formula (II-2) or its pharmaceutically acceptable salt;

in:

R ^w is alkyl, preferably ethyl;

T ¹ is C-NH ₂ ;

G ³ , G ⁴ , G ⁵ , G ⁶ , G ⁹ , R, R′, q and n are as defined in general formula (II-1) or (II-2).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (IIA) or its salt is subjected to cyclization reaction with the compound of general formula (IIIB) or its salt to obtain the compound of general formula (III) or its pharmaceutically acceptable salt;

in:

R ^w is alkyl, preferably ethyl;

T ¹ is C-NH ₂ ;

G3, G4, ^G5 , ^G6 , ^G9 , ^R , R', q and n are as defined in general ^formula (III).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (III) or a pharmaceutically acceptable salt thereof is separated to obtain a compound represented by general formula (III-1) or (III-2) or a pharmaceutically acceptable salt thereof;

in:

T ¹ , G ³ , G ⁴ , G ⁵ , G ⁶ , G ⁹ , R, R′, q and n are as defined in general formula (III-1) or (III-2).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (II-1A) or its salt is subjected to cyclization reaction with the compound of general formula (IIIB) or its salt to obtain the compound of general formula (III-1) or its pharmaceutically acceptable salt; or

The compound of general formula (II-2A) or its salt is subjected to cyclization reaction with the compound of general formula (IIIB) or its salt to obtain the compound of general formula (III-2) or its pharmaceutically acceptable salt;

in:

R ^w is alkyl, preferably ethyl;

T ¹ is C-NH ₂ ;

G ³ , G ⁴ , G ⁵ , G ⁶ , G ⁹ , R, R′, q and n are as defined in general formula (III-1) or (III-2).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (IC) or its salt is subjected to deprotection reaction to obtain the compound of general formula (I) or its pharmaceutically acceptable salt;

in:

R ^m is an amino protecting group; preferably Boc;

G ⁹ is NH;

Rings A, T ¹ , R′, R ⁰ , G ¹ to G ⁸ , R, q and n are as defined in general formula (I).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or (III) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (IIC) or a salt thereof is subjected to a deprotection reaction to obtain a compound of general formula (II) or a pharmaceutically acceptable salt thereof; or

The compound of general formula (IIIC) or its salt is subjected to deprotection reaction to obtain the compound of general formula (III) or its pharmaceutically acceptable salt;

in:

R ^m is an amino protecting group; preferably Boc;

G ⁹ is NH;

T ¹ , R′, G ³ to G ⁶ , R, q and n are as defined in general formula (II) or (III).

Another aspect of the present disclosure relates to a pharmaceutical composition comprising the general formulae (I), (I-1), (I-2), (II), (II-1), ( II-2), (III), (III-1), (III-2) and a compound shown in Table A or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, dilutions agent or excipient.

The present disclosure further relates to general formulae (I), (I-1), (I-2), (II), (II-1), (II-2), (III), (III-1), (III) -2) Use of a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for inhibiting HPK1.

The present disclosure further relates to general formulae (I), (I-1), (I-2), (II), (II-1), (II-2), (III), (III-1), (III) -2) Use of a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for a disease or condition for treatment and/or prevention by inhibiting HPK1; Said disease or condition is preferably selected from the group consisting of cancer, autoimmune disease, inflammatory disease, infectious disease, cardiovascular disease, neurodegenerative disease, diabetes, and reproductive disorders. Use in the medicament of a disease or condition; more preferably, Said disease or condition is selected from cancer, allergy, asthma, sepsis, HIV infection, hepatitis B virus infection, ischemia, atherosclerosis, stroke and Alzheimer's disease; said cancer is preferably selected from brain cancer , Thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophagus cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small bowel cancer, gastrointestinal stromal tumor, urinary tract Skin cancer, urethral cancer, bladder cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, Soft tissue sarcomas, neurofibromas, gliomas, neuroblastomas, and glioblastomas.

The present disclosure further relates to general formulae (I), (I-1), (I-2), (II), (II-1), (II-2), (III), (III-1), (III) -2) The compounds shown in Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same are prepared for the treatment and/or prevention of cancer, autoimmune diseases, inflammatory diseases, infectious diseases, Use in medicine for a disease or condition of cardiovascular disease, neurodegenerative disease, diabetes and reproductive disorders; preferably, said disease or condition is selected from cancer, allergy, asthma, sepsis, HIV infection, hepatitis B virus infection, ischemia, atherosclerosis, stroke and Alzheimer's disease; the cancer is preferably selected from brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophagus cancer, stomach cancer, lung cancer, liver cancer , kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small bowel cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, fallopian tube cancer, Testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma.

The present disclosure further relates to a method of inhibiting HPK1 comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), (I-1), (I-2), (II), (II-1), ( II-2), (III), (III-1), (III-2) and the compounds shown in Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same.

The present disclosure further relates to a method of treating and/or preventing a disease or condition, preferably a method of treating and/or preventing a disease or condition being treated and/or prevented by inhibiting HPK1, comprising administering to a patient in need thereof a therapeutically effective amount of General formula (I), (I-1), (I-2), (II), (II-1), (II-2), (III), (III-1), (III-2) and The compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; wherein the disease or condition is preferably selected from cancer, autoimmune disease, inflammatory disease, infectious disease, cardiovascular disease , neurodegenerative diseases, diabetes and reproductive disorders; more preferably, the disease or condition is selected from cancer, allergy, asthma, sepsis, HIV infection, hepatitis B virus infection, ischemia, atherosclerosis, stroke and Alzheimer's disease Zheimer's disease; the cancer is preferably selected from brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophagus cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colon cancer Rectal cancer, small bowel cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, Multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma, and glioblastoma.

The present disclosure further relates to a method of treating and/or preventing a disease or condition of cancer, autoimmune disease, inflammatory disease, infectious disease, cardiovascular disease, neurodegenerative disease, diabetes, and reproductive disorders, comprising administering the A therapeutically effective amount of formula (I), (I-1), (I-2), (II), (II-1), (II-2), (III), (III-1), The compound shown in (III-2) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; preferably, the disease or condition is selected from cancer, allergy, asthma, sepsis, HIV infection , hepatitis B virus infection, ischemia, atherosclerosis, stroke and Alzheimer's disease; the cancer is preferably selected from brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophagus cancer, Gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small bowel cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer Cancer, Fallopian Tube Cancer, Testicular Cancer, Prostate Cancer, Leukemia, Lymphoma, Multiple Myeloma, Skin Cancer, Malignant Lipoma, Bone Cancer, Soft Tissue Sarcoma, Neurofibroma, Glioma, Neuroblastoma and Glioma blastoma.

The present disclosure further relates to a general formula (I), (I-1), (I-2), (II), (II-1), (II-2), (III), (III-1), (III-2) The compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a medicine.

The present disclosure further relates to a general formula (I), (I-1), (I-2), (II), (II-1), (II-2), (III), (III-1), (III-2) The compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which are used as a drug for inhibiting HPK1.

The present disclosure further relates to a general formula (I), (I-1), (I-2), (II), (II-1), (II-2), (III), (III-1), The compound shown in (III-2) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, is used as a medicine for the treatment and/or prevention of a disease or condition, preferably for use as a treatment and/or Drugs for preventing diseases or conditions that are treated and/or prevented by inhibiting HPK1; wherein said diseases or conditions are preferably selected from cancer, autoimmune diseases, inflammatory diseases, infectious diseases, cardiovascular diseases, neurodegenerative diseases , diabetes and reproductive disorders; preferably, the disease or condition is selected from cancer, allergy, asthma, sepsis, HIV infection, hepatitis B virus infection, ischemia, atherosclerosis, stroke and Alzheimer's disease; Said cancer is preferably selected from brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophagus cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small bowel cancer, Gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin carcinoma, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma.

The present disclosure further relates to a general formula (I), (I-1), (I-2), (II), (II-1), (II-2), (III), (III-1), Compounds shown in (III-2) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in the treatment and/or prevention of cancer, autoimmune diseases, inflammatory diseases, infectious diseases , cardiovascular disease, neurodegenerative disease, diabetes and reproductive disorders; preferably, the disease or condition is selected from cancer, allergy, asthma, sepsis, HIV infection, hepatitis B virus infection, ischemia, arterial Atherosclerosis, stroke and Alzheimer's disease; the cancer is preferably selected from brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophagus cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, Pancreatic cancer, bile duct cancer, colorectal cancer, small bowel cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer Carcinoma, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma.

Preferably, the brain cancer described in the present disclosure is selected from glioblastoma multiforme or neuroblastoma; soft tissue cancer is selected from fibrosarcoma, gastrointestinal sarcoma, rhabdomyosarcoma, leiomyosarcoma, dedifferentiated liposarcoma, pleomorphic liposarcoma, malignant fibrous histiocytoma, round cell sarcoma, and synovial sarcoma; lymphoma selected from Hodgkin's disease and non-Hodgkin's lymphoma (eg, mantle cell lymphoma, diffuse large B-cell lymphoma , follicular center lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma and peripheral T-cell lymphoma); liver cancer is preferably hepatocellular carcinoma; lung cancer is selected from non-small cell lung cancer (NSCLC) (eg squamous cell carcinoma) ) and small cell lung cancer (SCLC); kidney cancer is selected from renal cell carcinoma, clear cell and renal oncocytoma; leukemia is selected from chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia, acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myeloid leukemia (CML) and acute myeloid leukemia (AML); skin cancer is selected from malignant melanoma, squamous cell carcinoma, basal cell carcinoma and angiosarcoma; throat cancer is selected from nasopharyngeal carcinoma.

The colorectal cancer described in the present disclosure is also called colorectal cancer, preferably colon cancer or rectal cancer; the uterine cancer is preferably endometrial cancer.

The active compounds can be formulated in a form suitable for administration by any suitable route, and the compositions of the present disclosure can be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure can be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular, or subcutaneous) administration, inhalation or insufflation. The compounds of the present disclosure may also be formulated in dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injectable solutions, dispersible powders or granules, suppositories, lozenges or syrups.

As a general guide, the active compounds of the present disclosure are preferably presented in unit dosage form or in a form that the patient can self-administer in a single dose. A unit dose of a compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, vial, powder, granule, lozenge, suppository, reconstituted powder, or liquid. A suitable unit dose may be 0.1 to 1000 mg.

In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait. Depending on the method of administration, the composition may contain from 0.1 to 99% by weight of active compound.

Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.

Oral formulations can also be presented in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble or oily vehicle.

Aqueous suspensions contain the active substances in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. The aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

Oily suspensions can be formulated by suspending the active ingredient in vegetable or mineral oils. The oily suspensions may contain thickening agents. The aforementioned sweetening and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase can be vegetable oil, or mineral oil or a mixture thereof. Suitable emulsifying agents may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Among the acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. A sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase. The injectable solution or microemulsion can be injected into the bloodstream of a patient by local bulk injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the present disclosure. To maintain this constant concentration, a continuous intravenous drug delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. In addition, sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blending and fixing oil can be used. In addition, fatty acids are also available in the preparation of injectables.

The compounds of the present disclosure can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.

The compounds of the present disclosure can be administered by the addition of water to prepare dispersible powders and granules for aqueous suspension. These pharmaceutical compositions can be prepared by admixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.

As is well known to those skilled in the art, the dosage of a drug to be administered depends on a variety of factors including, but not limited to, the activity of the particular compound used, the severity of the disease, the age of the patient, the weight of the patient, the health of the patient condition, behavior of the patient, diet of the patient, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; in addition, the optimal mode of treatment such as mode of treatment, daily dose of compound or pharmaceutically acceptable salt Species can be verified against conventional treatment protocols.

Glossary

Unless stated to the contrary, terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably 1 to 12 (eg 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 11 and 12) carbon atoms (ie C _1-20 alkyl), more preferably alkyl having 1 to 6 carbon atoms (ie C _1-6 alkyl) ). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2 -methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4- Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3- Ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof, etc. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylpropyl butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl base, 2,3-dimethylbutyl, etc. Alkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, haloalkoxy , one or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term "alkylene" refers to a saturated straight or branched chain aliphatic hydrocarbon group, which is a residue derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is a residue containing 1 straight or branched chain groups of up to 20 carbon atoms, preferably having 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms ( That is, a C _1-12 alkylene group), more preferably an alkylene group having 1 to 6 carbon atoms (ie, a C _1-6 alkylene group). Non-limiting examples of alkylene groups include, but are not limited to, methylene ( _-CH2- ), 1,1-ethylene (-CH( _CH3 )-), 1,2-ethylene (-CH ₂ CH ₂ )-, 1,1-propylene (-CH(CH ₂ CH ₃ )-), 1,2-propylene (-CH ₂ CH(CH ₃ )-), 1,3-propylene base (-CH ₂ CH ₂ CH ₂ -), 1,4-butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -) and the like. The alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from the group consisting of alkenyl, alkynyl, alkoxy, haloalkoxy, Cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy one or more of oxo, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.

The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the alkyl group is as defined above, preferably having 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (ie C _2-12 alkenyl), more preferably alkenyl having 2 to 6 carbon atoms (ie C _2-6 alkenyl). Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, and the like. Alkenyl can be substituted or unsubstituted, when substituted, the substituent is preferably selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl one or more of , cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term "alkynyl" refers to an alkyl group having at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Preferably have 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (ie C _2-12 alkynyl), more preferably have 2 to 6 Alkynyl of carbon atoms (ie C _2-6 alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl one or more of , cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 14 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14) carbon atoms (i.e. 3 to 14 membered cycloalkyl), preferably 3 to 8 (e.g. 3, 4, 5, 6, 7 and 8) ) carbon atoms (ie 3 to 8 membered cycloalkyl), more preferably 3 to 6 carbon atoms (ie 3 to 6 membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Polycyclic cycloalkyl groups include spirocycloalkyl groups, fused cycloalkyl groups and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group with one carbon atom (called a spiro atom) shared between the monocyclic rings, which may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of shared spiro atoms between the rings, spirocycloalkyl groups are classified as mono- or poly-spirocycloalkyl groups (eg, bis-spirocycloalkyl groups), preferably mono-spirocycloalkyl groups and bis-spirocycloalkyl groups base. More preferably 3 yuan/4 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan , 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan Member/5-membered or 7-membered/6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:

The term "fused cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more Multiple double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic or polycyclic (such as tricyclic, tetracyclic) fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/membered 6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan , 6-member/3-member, 6-member/4-member, 6-member/5-member, 6-member/6-member, 6-member/7-member, 7-member/5-member or 7-member/6-membered bicyclic fused cycloalkyl. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly attached carbon atoms, which may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic or polycyclic (eg tricyclic, tetracyclic) bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

等；优选为

The cycloalkyl ring includes a cycloalkyl (including monocyclic, spiro, fused and bridged) as described above fused to an aryl, heteroaryl or heterocycloalkyl ring where it is attached to the parent structure Rings together are cycloalkyl, non-limiting examples include

etc.; preferably

Cycloalkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy One or more of hydroxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy. Alkoxy can be optionally substituted or unsubstituted, when substituted, the substituent is preferably selected from D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy group, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent comprising 3 to 20 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e. 3 to 20 membered heterocyclyl), wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, so Said sulfur may optionally be oxo (ie, to form a sulfoxide or sulfone), but does not include ring moieties of -O-O-, -O-S- or -S-S-, the remaining ring atoms being carbon. It preferably contains 3 to 14 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14) ring atoms (ie 3 to 14 membered heterocyclyl), of which 1 to 4 (eg 1, 2, 3 and 4) are heteroatoms; more preferably 3 to 8 ring atoms (eg 3, 4, 5, 6, 7 and 8) are included (ie 3 to 8 membered heterocyclyl) or 6 to 14 ring atoms (e.g. 6, 7, 8, 9, 10, 11, 12, 13 and 14) of which 1-3 are heteroatoms (e.g. 1, 2 and 3); more preferably including 3 Up to 8 ring atoms, of which 1-3 (eg, 1, 2, and 3) are heteroatoms; most preferably 5 or 6 ring atoms, of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholine base, homopiperazinyl, etc. Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.

The term "spiroheterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclic group with one atom (called a spiro atom) shared between the single rings, wherein one or more ring atoms are selected from nitrogen, oxygen and sulfur. A heteroatom, the sulfur may optionally be oxo (ie to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably it is 6 to 14 membered (eg 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered) (ie 6 to 14 membered spiroheterocyclyl), more preferably 7 to 10 membered (eg 7, 8, 9 or 10 membered) (ie 7 to 10 membered spiroheterocyclyl). Spiroheterocyclyls are classified into mono- or poly-spiroheterocyclyls (eg, bis-spiroheterocyclyls) according to the number of spiro atoms shared between the rings, preferably mono-spiroheterocyclyls and bis-spiroheterocyclyls base. More preferably 3 yuan/4 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan , 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan Member/5-membered or 7-membered/6-membered single spiro heterocyclyl. Non-limiting examples of spiroheterocyclyl include:

The term "fused heterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more of the rings may contain one or more Double bonds in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which may be optionally oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably it is 6 to 14 membered (eg 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered) (ie 6 to 14 membered fused heterocyclic group), more preferably 7 to 10 membered (eg 7, 8, 9 or 10 membered) (ie 7 to 10 membered fused heterocyclyl). According to the number of constituent rings, it can be divided into bicyclic or polycyclic (such as tricyclic, tetracyclic) fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/membered 6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan , 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:

The term "bridged heterocyclyl" refers to a 5- to 20-membered, polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, in which one or more ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which may optionally be oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably it is 6 to 14 membered (eg 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered) (ie 6 to 14 membered bridged heterocyclyl), more preferably 7 to 10 membered (eg 7, 8, 9 or 10 membered) (ie, a 7- to 10-membered bridged heterocyclyl). According to the number of constituent rings, it can be divided into bicyclic or polycyclic (eg tricyclic, tetracyclic) bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

The heterocyclyl ring includes a heterocyclyl group (including monocyclic, spiroheterocycle, fused heterocycle and bridged heterocycle) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the The rings to which the structure is attached are heterocyclyl, non-limiting examples of which include:

等。

Wait.

Heterocyclyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy One or more of hydroxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic are rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 10 membered , such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include :

Aryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy , one or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms (eg 1, 2, 3 and 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered (eg 5, 6, 7, 8, 9 or 10 membered) (ie 5 to 10 membered heteroaryl), more preferably 5 or 6 membered, such as furyl, thienyl , pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include :

Heteroaryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy one or more substituents in the group consisting of radical, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl .

The above cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived by removing one hydrogen atom from the parent ring atom, or removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent The residues from which atoms are derived are "divalent cycloalkyl", "divalent heterocyclyl", "arylene" and "heteroarylene".

The term "amino protecting group" is used to protect the amino group with a group that is easy to remove in order to keep the amino group unchanged when the other part of the molecule is reacted. Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro.

The term "hydroxy protecting group" refers to a hydroxy derivative commonly used to block or protect a hydroxy group while reacting on other functional groups of a compound. As an example, preferably, the hydroxyl protecting group can be triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, methyl , tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitro benzoyl.

The term "cycloalkyloxy" refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.

The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

The term "aryloxy" refers to aryl-O-, wherein aryl is as defined above.

The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

The term "alkylthio" refers to alkyl-S-, wherein alkyl is as defined above.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "hydroxy" refers to -OH.

The term "thiol" refers to -SH.

The term "amino" refers to _-NH2 .

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

The term "oxo" or "oxo" refers to "=O".

The term "carbonyl" refers to C=O.

The term "carboxy" refers to -C(O)OH.

The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, wherein alkyl and cycloalkyl are as defined above.

The compounds of the present disclosure may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers that are structurally identical but differ in the arrangement of the atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (e.g. racemates, mixtures of diastereomers) . Substituents in the compounds of the present disclosure may have additional asymmetric atoms. All such stereoisomers, as well as mixtures thereof, are included within the scope of this disclosure. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (D)- and (+)-isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques (L)-isomer. An isomer of a certain compound of the present disclosure can be prepared by asymmetric synthesis or chiral auxiliaries, or, when the molecule contains basic functional groups (such as amino groups) or acidic functional groups (such as carboxyl groups), with appropriate optical Active acids or bases form diastereomeric salts, which are then resolved by conventional methods known in the art to yield the pure isomers. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by chromatography.

表示未指定构型，即如果化学结构中存在手性异构体，键

可以为

或

或者同时包含

和

两种构型。In the chemical structure of the compound described in the present disclosure, the bond

Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond

can be

or

or both

and

Two configurations.

The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as proton tautomers) include interconversion via proton transfer, such as keto-enol and imine-enamine, lactam-lactam isomerizations . An example of a keto-enol equilibrium is between A and B as shown below.

As another example, when referring to imidazolyl, it should be understood to include either one of the following two structures or a mixture of two tautomers.

All tautomeric forms are within the scope of this disclosure. The naming of compounds does not exclude any tautomers.

The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be incorporated into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, such as ² H (deuterium, D), respectively, ³ H (tritium, T), ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³² p, ³³ p, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹²⁹ I and ¹³¹ I, etc., preferably deuterium.

Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic and side effects, increasing drug stability, enhancing curative effect, and prolonging the biological half-life of drugs. All transformations of the isotopic composition of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom, wherein the replacement of deuterium can be partial or complete, and a partial replacement of deuterium means that at least one hydrogen is replaced by at least one deuterium.

"Optionally" or "optionally" means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance occurs or instances where it does not. For example, "C _1-6 alkyl optionally substituted by halogen or cyano" means that halogen or cyano may but need not be present, and the description includes the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano substitution.

"Substituted" means that one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. A person skilled in the art can determine possible or impossible substitutions (either experimentally or theoretically) without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.

"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.

"Pharmaceutically acceptable salt" refers to a salt of a compound of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals, and have due biological activity. The salts can be prepared separately during the final isolation and purification of the compounds, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation, allergic response or Other problems or complications with a reasonable benefit/risk ratio and are effective for the intended use.

As used herein, the singular forms "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is indicated that the parameter can vary by ±10%, and is sometimes more preferably within ±5%. As those skilled in the art will understand, when parameters are not critical, numbers are generally given for illustrative purposes only, and not limitations.

Synthetic methods of compounds of the present disclosure

In order to accomplish the purpose of the present disclosure, the present disclosure adopts the following technical solutions:

Option One

The preparation method of the compound represented by the general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:

The compound of general formula (IA) or its salt is subjected to cyclization reaction with the compound of general formula (IB) or its salt under basic conditions to obtain the compound of general formula (I) or its pharmaceutically acceptable salt;

in:

R ^w is alkyl, preferably ethyl;

T ¹ is C-NH ₂ ;

Rings A, R ⁰ , R', q, G ¹ to G ⁹ , R and n are as defined in general formula (I).

Option II

The present disclosure is a preparation method of a compound represented by general formula (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (I) or its pharmaceutically acceptable salt is obtained by chiral preparation and resolution to obtain the compound represented by general formula (I-1) or (I-2) or its pharmaceutically acceptable salt;

in:

Rings A, T ¹ , R ⁰ , R′, q, G ¹ to G ⁹ , R and n are as defined in general formula (I-1) or (I-2).

third solution

The present disclosure is a preparation method of a compound represented by general formula (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (I-1A) or its salt is subjected to cyclization reaction with the compound of general formula (IB) or its salt under basic conditions to obtain the compound of general formula (I-1) or its pharmaceutically acceptable salt ;or

The compound of general formula (I-2A) or its salt is subjected to cyclization reaction with the compound of general formula (IB) or its salt under basic conditions to obtain the compound of general formula (I-2) or its pharmaceutically acceptable salt ;

in:

R ^w is alkyl, preferably ethyl;

T ¹ is C-NH ₂ ;

Rings A, R ⁰ , R', q, G ¹ to G ⁹ , R and n are as defined in general formula (I-1) or (I-2).

Option 4

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (IIA) or its salt is subjected to cyclization reaction with the compound of general formula (IIB) or its salt under basic conditions to obtain the compound of general formula (II) or its pharmaceutically acceptable salt;

in:

R ^w is alkyl, preferably ethyl;

T ¹ is C-NH ₂ ;

G3, G4, ^G5 , ^G6 , ^G9 , ^R , R', q and n are as defined in general ^formula (II).

Option five

The present disclosure is a preparation method of a compound represented by general formula (II-1) or (II-2) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (II) or its pharmaceutically acceptable salt is obtained by chiral preparation and resolution to obtain the compound represented by general formula (II-1) or (II-2) or its pharmaceutically acceptable salt;

in:

T ¹ , G ³ , G ⁴ , G ⁵ , G ⁶ , G ⁹ , R, R′, q and n are as defined in general formula (II-1) or (II-2).

Option 6

The present disclosure is a preparation method of a compound represented by general formula (II-1) or (II-2) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (II-1A) or its salt is subjected to cyclization reaction with the compound of general formula (IIB) or its salt under basic conditions to obtain the compound of general formula (II-1) or its pharmaceutically acceptable salt ;or

The compound of general formula (II-2A) or its salt and the compound of general formula (IIB) or its salt undergo cyclization reaction under basic conditions to obtain the compound of general formula (II-2) or its pharmaceutically acceptable salt ;

in:

R ^w is alkyl, preferably ethyl;

T ¹ is C-NH ₂ ;

G ³ , G ⁴ , G ⁵ , G ⁶ , G ⁹ , R, R′, q and n are as defined in general formula (II-1) or (II-2).

Option 7

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (IIA) or its salt is subjected to cyclization reaction with the compound of general formula (IIIB) or its salt under basic conditions to obtain the compound of general formula (III) or its pharmaceutically acceptable salt;

in:

R ^w is alkyl, preferably ethyl;

T ¹ is C-NH ₂ ;

G3, G4, ^G5 , ^G6 , ^G9 , ^R , R', q and n are as defined in general ^formula (III).

Option 8

The present disclosure is a preparation method of a compound represented by general formula (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (III) or its pharmaceutically acceptable salt is obtained by chiral preparation and resolution to obtain the compound represented by general formula (III-1) or (III-2) or its pharmaceutically acceptable salt;

in:

T ¹ , G ³ , G ⁴ , G ⁵ , G ⁶ , G ⁹ , R, R′, q and n are as defined in general formula (III-1) or (III-2).

Option Nine

The present disclosure is a preparation method of a compound represented by general formula (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (II-1A) or its salt is subjected to cyclization reaction with the compound of general formula (IIIB) or its salt under basic conditions to obtain the compound of general formula (III-1) or its pharmaceutically acceptable salt ;or

The compound of general formula (II-2A) or its salt and the compound of general formula (IIIB) or its salt undergo cyclization reaction under basic conditions to obtain the compound of general formula (III-2) or its pharmaceutically acceptable salt ;

in:

R ^w is alkyl, preferably ethyl;

T ¹ is C-NH ₂ ;

G ³ , G ⁴ , G ⁵ , G ⁶ , G ⁹ , R, R′, q and n are as defined in general formula (III-1) or (III-2).

Option ten

The preparation method of the compound represented by the general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:

The compound of general formula (IC) or its salt is subjected to deprotection reaction under acidic conditions to obtain the compound of general formula (I) or its pharmaceutically acceptable salt;

in:

R ^m is an amino protecting group; preferably Boc;

G ⁹ is NH;

Rings A, T ¹ , R′, R ⁰ , G ¹ to G ⁸ , R, q and n are as defined in general formula (I).

Plan Eleven

The preparation method of the compound represented by the general formula (II) or (III) of the present disclosure or a pharmaceutically acceptable salt thereof, the method comprises:

The compound of general formula (IIC) or its salt is subjected to deprotection reaction under acidic conditions to obtain the compound of general formula (II) or its pharmaceutically acceptable salt; or

The compound of general formula (IIIC) or its salt is subjected to deprotection reaction under acidic conditions to obtain the compound of general formula (III) or its pharmaceutically acceptable salt;

in:

R ^m is an amino protecting group; preferably Boc;

G ⁹ is NH;

T ¹ , R′, G ³ to G ⁶ , R, q and n are as defined in general formula (II) or (III).

The reagents that provide basic conditions in the above synthesis scheme include organic bases and inorganic bases, and the organic bases include but are not limited to triethylamine, pyridine, N,N-diisopropylethylamine, n-butyllithium, Lithium diisopropylamide, tetrahydrofuran solution of lithium diisopropylamide, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide, bis(trimethyl) Silicon) Lithium Lithium Tetrahydrofuran solution or 1,8-diazabicycloundec-7-ene, the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate , sodium hydroxide, lithium hydroxide and potassium hydroxide; preferably lithium diisopropylamide or lithium diisopropylamide in tetrahydrofuran.

The reagents providing acidic conditions in the above synthesis scheme include organic acids and inorganic acids, and the organic acids include but are not limited to trifluoroacetic acid, formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, Me ₃ SiCl and TMSOTf; the The inorganic acids used include, but are not limited to, hydrogen chloride, hydrogen chloride in 1,4-dioxane, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; preferably trifluoroacetic acid.

The reaction of the above steps is preferably carried out in a solvent, and the solvent used includes but is not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, Ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromo Ethane and mixtures thereof.

Detailed ways

The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.

Example

The structures of the compounds were determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10<" ⁶ > (ppm). NMR was measured by Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was four Methylsilane (TMS).

The MS was measured with a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQadvantage MAX).

High Performance Liquid Chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC1200VWD and a Waters HPLC e2695-2489 High Performance Liquid Chromatograph.

Chiral HPLC analysis was determined using an Agilent 1260DAD high performance liquid chromatograph.

High performance liquid phase preparations used Waters 2767, Waters 2767-SQ Detector2, Shimadzu LC-20AP and Gilson-281 preparative chromatographs.

Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

The CombiFlash rapid preparation instrument used Combiflash Rf200 (TELEDYNE ISCO).

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ~ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ~0.5mm.

Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

The average inhibition rate and IC ₅₀ value of kinases were measured with NovoStar microplate reader (BMG, Germany).

The known starting materials of the present invention can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals products and other companies.

There is no special description in the examples, and the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere.

Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.

Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.

The pressurized hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.

The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.

The microwave reaction used a CEM Discover-S 908860 microwave reactor.

There is no special description in the examples, and the solution refers to an aqueous solution.

There is no special description in the examples, and the reaction temperature is room temperature, which is 20°C to 30°C.

The monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of the column chromatography used for purifying the compound and the developing solvent system of the thin layer chromatography method include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: n-hexane/dichloromethane system, D: ethyl acetate/dichloromethane/n-hexane, the volume ratio of the solvent varies according to the polarity of the compound For adjustment, a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

Example 1

4-Amino-5-(3-methyl-2,3,4,4a,5,6-hexahydro-1H,11H-imidazo[4',5':4,5]benzo[1,2 -b]pyrazino[1,2-d][1,4]oxazepan-10-yl)thieno[2,3-b]pyridin-6(7H)-one 1

first step

9,10-Dinitro-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazepine Alkane-3-carboxylate tert-butyl ester 1c

Compound 1,2-difluoro-4,5-dinitrobenzene 1a (1 g, 4.3 mmol, Shanghai Bide), 3-(2-hydroxyethyl)piperazine-1-carboxylate tert-butyl ester 1b ( 1.32g, 6.5mmol), potassium hydroxide (730mg, 13mmol) was dissolved in 30mL of dimethyl sulfoxide, first reacted at 30°C for 3 hours, then heated to 60°C and reacted for 5 hours, 50mL of water was added to the reaction solution, After extraction with ethyl acetate (30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate was concentrated under reduced pressure, and purified by column chromatography with eluent system B to obtain the title compound 1c (1.2 g, yield: 70%).

MS m/z (ESI): 395.2 [M-H].

second step

9,10-Dinitro-2,3,4,4a,5,6-hexahydro-1H-benzo[b]pyrazino[1,2-d][1,4]oxazepine Alkane 1d

Compound 1c (1.2 g, 3.04 mmol) was dissolved in 20 mL of dichloromethane, 3 mL of trifluoroacetic acid was added, and after stirring for 1 hour, the reaction solution was concentrated under reduced pressure to obtain the crude title product 1d (0.89 g), the product The next reaction was carried out directly without purification.

MS m/z (ESI): 295.1 [M+1].

third step

3-Methyl-9,10-dinitro-2,3,4,4a,5,6-hexahydro-1H-benzo[b]pyrazino[1,2-d][1,4] oxazepane 1e

Compound 1d (890 mg, 3.02 mmol) was dissolved in 20 mL of methanol, 3 mL of 37% aqueous formaldehyde solution and three drops of acetic acid were added, and after stirring the reaction for 1 hour, sodium cyanoborohydride (271.38 mg, 4.53 mmol) was added, and the reaction was stirred for 14 After one hour, the reaction solution was concentrated under reduced pressure, and purified by column chromatography with eluent system A to obtain the title compound 1e (600 mg, yield: 60%).

MS m/z (ESI): 309.1 [M+1].

the fourth step

2-(3-Methyl-2,3,4,4a,5,6-hexahydro-1H,9H-imidazo[4',5':4,5]benzo[1,2-b]pyridine Azino[1,2-d][1,4]oxazepan-10-yl)ethyl acetate 1g

Compound 1e (600 mg, 1.94 mmol), 3-ethoxy-3-iminopropionic acid ethyl ester hydrochloride 1f (1.14 g, 5.83 mmol, Shanghai Hanhong) was dissolved in 50 mL of absolute ethanol, and 10% palladium was added. Carbon catalyst (200 mg), replaced with hydrogen, stirred and reacted for 14 hours, heated to 70°C for 2 hours, the reaction solution was filtered, concentrated under reduced pressure, and purified by column chromatography with eluent system A to obtain 1 g of the title compound (350 mg, yield rate: 52.2%).

MS m/z (ESI): 345.2 [M+1].

the fifth step

4-Amino-5-(3-methyl-2,3,4,4a,5,6-hexahydro-1H,11H-imidazo[4',5':4,5]benzo[1,2 -b]pyrazino[1,2-d][1,4]oxazepan-10-yl)thieno[2,3-b]pyridin-6(7H)-one 1

Compound 2-aminothiophene-3-carbonitrile 1h (65mg, 523.50μmol), compound 1g (120mg, 348.42μmol) was dissolved in 10mL of tetrahydrofuran, and 1.16mL of 2M tetrahydrofuran solution of lithium diisopropylamide was added to stir the reaction 14 Concentrate under reduced pressure after 1 hour, and use high performance liquid chromatography (Waters-2545, chromatographic column: SharpSil-T C18, 30*150 mm, 5 μm; mobile phase 1: water (10 mmol/L ammonium bicarbonate); mobile phase 2: acetonitrile , 20 minutes gradient ratio: 25%-42%, flow rate: 30 mL/min) and purified to obtain the title compound 1 (10 mg, yield: 6.79%).

MS m/z (ESI): 423.2 [M+1].

¹ H NMR (500MHz, DMSO-d ₆ ): δ 12.59(d,1H), 12.08(s,1H), 10.63(d,1H), 7.96(s,1H), 7.59(dd,1H), 7.33 -7.01(m,3H),4.49-4.36(m,1H),4.09-4.02(m,1H),3.18(m,1H),3.11(m,1H),3.00-2.74(m,3H),2.29 (s, 3H), 2.08-1.95 (m, 2H), 1.73 (t, 2H).

Example 1-1, 1-2

(R)-4-Amino-5-(3-methyl-2,3,4,4a,5,6-hexahydro-1H,11H-imidazo[4',5':4,5]benzo [1,2-b]pyrazino[1,2-d][1,4]oxazepan-10-yl)thieno[2,3-b]pyridin-6(7H)-one 1-1

(S)-4-Amino-5-(3-methyl-2,3,4,4a,5,6-hexahydro-1H,11H-imidazo[4',5':4,5]benzo [1,2-b]pyrazino[1,2-d][1,4]oxazepan-10-yl)thieno[2,3-b]pyridin-6(7H)-one 1-2

(R)-4-Amino-5-(3-methyl-2,3,4,4a,5,6-hexahydro-1H,11H-imidazo[4',5':4,5]benzo [1,2-b]pyrazino[1,2-d][1,4]oxazepan-10-yl)thieno[2,3-b]pyridin-6(7H)-one 1-1

(S)-4-Amino-5-(3-methyl-2,3,4,4a,5,6-hexahydro-1H,11H-imidazo[4',5':4,5]benzo [1,2-b]pyrazino[1,2-d][1,4]oxazepan-10-yl)thieno[2,3-b]pyridin-6(7H)-one 1-2

Compound 1 (180 mg, 426.54 μmol) was chiral prepared (separation conditions: chiral preparative column CHIRALPAKIE 20*250 mm, 5 μm; mobile phase 1: n-hexane; mobile phase 2: ethanol (10 mmol/L ammonia), flow rate: 20 mL /min), the corresponding fractions were collected and concentrated under reduced pressure to give the title compounds 1-1 (70 mg, yield: 8.1%), 1-2 (65 mg, yield: 8.1%).

Single configuration compound 1-1 (shorter retention time):

MS m/z (ESI): 423.2 [M+1].

Chiral HPLC analysis: retention time 12.19 minutes, chiral purity: 98% (chromatographic column: CHIRALPAK IE 4.6*150mm, 5μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), ethanol 80% ratio elution , flow rate: 1.0mL/min).

¹ H NMR (500MHz, DMSO-d ₆ ): δ 12.59(d,1H), 12.11(s,1H), 10.63(d,1H), 7.96(s,1H), 7.59(dd,1H), 7.33 -7.01(m, 3H), 4.47-4.43(m, 1H), 4.07-4.05(m, 1H), 3.17(m, 1H), 3.12(m, 1H), 3.03-2.74(m, 3H), 2.29 (s, 3H), 2.08-1.95 (m, 2H), 1.73 (t, 2H). Single configuration compound 1-2 (longer retention time):

MS m/z (ESI): 423.2 [M+1].

Chiral HPLC analysis: retention time 15.64 minutes, chiral HPLC analysis: chiral purity: 95% (chromatographic column: CHIRALPAK IE 4.6*150mm, 5μm; mobile phase: n-hexane, ethanol (containing 0.1% diethylamine), ethanol 80% ratio elution, flow rate: 1.0 mL/min).

¹ H NMR (500MHz, DMSO-d ₆ ): δ 12.60(d,1H), 12.08(s,1H), 10.63(d,1H), 7.95(s,1H), 7.58(dd,1H), 7.18 -7.02(m,3H),4.45-4.40(m,1H),4.07-4.03(m,1H),3.18(m,1H),3.11(m,1H),3.00-2.77(m,3H),2.29 (s, 3H), 2.08-1.95 (m, 2H), 1.73 (t, 2H).

Example 2

4-Amino-3-(3-methyl-2,3,4,4a,5,6-hexahydro-1H,11H-imidazo[4',5':4,5]benzo[1,2 -b]pyrazino[1,2-d][1,4]oxazepan-10-yl)quinolin-2(1H)-one 2

Using the synthetic route in Example 1, the starting material compound 1h of the fifth step was replaced with compound 2-aminobenzonitrile to obtain the title compound 2 (10 mg, yield: 10.33%).

MS m/z (ESI): 417.2 [M+1].

¹ H NMR (500 MHz, CD ₃ OD): δ 8.11 (dd, 1H), 7.60 (ddd, 1H), 7.39-7.34 (m, 1H), 7.33-7.11 (m, 3H), 4.62-4.47 (m ,1H),4.14(dt,1H),3.23(s,2H),3.00(s,2H),2.80(d,1H),2.52(s,1H),2.44(s,4H),2.15(s, 1H), 1.76(d, 1H).

Example 3

4-Amino-5-fluoro-3-(3-methyl-2,3,4,4a,5,6-hexahydro-1H,11H-imidazo[4',5':4,5]benzo [1,2-b]pyrazino[1,2-d][1,4]oxazepan-10-yl)quinolin-2(1H)-one 3

(R)-4-Amino-5-fluoro-3-(3-methyl-2,3,4,4a,5,6-hexahydro-1H,11H-imidazo[4',5':4, 5] Benzo[1,2-b]pyrazino[1,2-d][1,4]oxazepan-10-yl)quinolin-2(1H)-one 3-1

(S)-4-Amino-5-fluoro-3-(3-methyl-2,3,4,4a,5,6-hexahydro-1H,11H-imidazo[4',5':4, 5] Benzo[1,2-b]pyrazino[1,2-d][1,4]oxazepan-10-yl)quinolin-2(1H)-one 3-2

Using the synthetic route in Example 1, the raw material compound 1h of the fifth step was replaced with compound 2-amino-6-fluorobenzonitrile 3a to obtain the title compound 3 (40 mg, yield: 7.9%), which was then subjected to chiral preparation (separation of Conditions: instrument: GILSON 281; chromatographic column: CHIRALPAK IE 250*20mm, 5μm; mobile phase: ethanol (containing 0.1% diethylamine: 100%), the corresponding fractions were collected and concentrated under reduced pressure to obtain the title compound 3- 1 (10 mg, yield: 1.98%), 3-2 (7 mg, yield: 1.38%).

Single configuration compound 3-1 (shorter retention time):

MS m/z (ESI): 435.2 [M+1].

Chiral HPLC analysis: retention time 29.01 minutes, purity: 94% (chromatographic column: CHIRALPAK IE150*4.6 mm, 5 μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), flow rate: 1.0 mL/min). ¹ H NMR (500MHz, CD ₃ OD): δ 7.55 (td, 1H), 7.31-7.09 (m, 3H), 7.01 (dd, 1H), 4.59-4.48 (m, 1H), 4.14 (dt, 1H) ), 3.32-3.23(m, 3H), 3.00(s, 2H), 2.80(d, 1H), 2.51(t, 1H), 2.44(s, 3H), 2.15(s, 1H), 1.76(d, 1H).

Single configuration compound 3-2 (longer retention time):

MS m/z (ESI): 435.2 [M+1].

Chiral HPLC analysis: retention time 37.89 minutes, purity: 90% (chromatographic column: CHIRALPAK IE150*4.6 mm, 5 μm; mobile phase: n-hexane, ethanol (containing 0.1% diethylamine), flow rate: 1.0 mL/min). ¹ H NMR (500MHz, CD ₃ OD): δ 7.55 (td, 1H), 7.32-7.10 (m, 3H), 7.01 (dd, 1H), 4.61-4.49 (m, 1H), 4.14 (dt, 1H) ),3.27(s,3H),3.01(s,2H),2.81(d,1H),2.53(t,1H),2.45(s,3H),2.15(s,1H),1.76(d,1H) .

Example 4

4-Amino-5-(2,3,4,4a,5,6-hexahydro-1H,11H-imidazo[4',5':4,5]benzo[1,2-b]pyrazine Do[1,2-d][1,4]oxazepan-10-yl)thieno[2,3-b]pyridin-6(7H)-one 4

(R)-4-Amino-5-(2,3,4,4a,5,6-hexahydro-1H,11H-imidazo[4',5':4,5]benzo[1,2- b]pyrazino[1,2-d][1,4]oxazepan-10-yl)thieno[2,3-b]pyridin-6(7H)-one 4-1

(S)-4-Amino-5-(2,3,4,4a,5,6-hexahydro-1H,11H-imidazo[4',5':4,5]benzo[1,2- b]pyrazino[1,2-d][1,4]oxazepan-10-yl)thieno[2,3-b]pyridin-6(7H)-one 4-2

first step

10-(2-Ethoxy-2-oxoethyl)-1,2,4,4a,5,6-hexahydro-3H,9H-imidazo[4',5':4,5]benzo [1,2-b]pyrazino[1,2-d][1,4]oxazepane-3-carboxylate tert-butyl ester 4a

Compound 1c (600 mg, 1.94 mmol), compound 1f (1.14 g, 5.83 mmol, Shanghai Hanhong) were dissolved in absolute ethanol (50 mL), 10% palladium-carbon catalyst (wet) (200 mg) was added, hydrogen was replaced, and the reaction was stirred. After 14 hours, the reaction was heated to 70°C for 2 hours. The reaction solution was filtered, concentrated under reduced pressure, and purified by column chromatography with eluent system A to obtain the title compound 4a (350 mg, yield: 52.2%).

MS m/z (ESI): 431.2 [M+1].

second step

10-(4-Amino-6-oxy-6,7-dihydrothiophene[2,3-b]pyridin-5-yl)-1,2,4,4a,5,6-hexahydro-3H, 11Himidazo[4',5':4,5]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazepan-3-carboxylate tert-butyl Ester 4b

Compound 1h (65 mg, 523.50 μmol) and compound 4a (120 mg, 348.42 μmol) were dissolved in tetrahydrofuran (10 mL), and a 2.0 M solution of lithium diisopropylamide in tetrahydrofuran (1.16 mL) was added, and the reaction was stirred for 14 hours and then reduced It was concentrated under pressure and purified by column chromatography with eluent system A to give the title compound 4b (10 mg, yield: 6.79%).

MS m/z (ESI): 509.2 [M+1].

third step

(R)-4-Amino-5-(2,3,4,4a,5,6-hexahydro-1H,11H-imidazo[4',5':4,5]benzo[1,2- b]pyrazino[1,2-d][1,4]oxazepan-10-yl)thieno[2,3-b]pyridin-6(7H)-one 4-1

(S)-4-Amino-5-(2,3,4,4a,5,6-hexahydro-1H,11H-imidazo[4',5':4,5]benzo[1,2- b]pyrazino[1,2-d][1,4]oxazepan-10-yl)thieno[2,3-b]pyridin-6(7H)-one 4-2

Compound 4b (200 mg, 393.2 μmol) was dissolved in dichloromethane (20 mL), 5 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 0.5 hour. After the reaction solution was concentrated under reduced pressure, the residue was subjected to high-performance liquid chromatography (Waters-2545, chromatography). Column: SharpSil-T C18, 30*150mm, 5μm; mobile phase: water (10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30mL/min) purification to obtain the title compound 4 (80 mg, yield: 49.5%), and then perform chiral preparation (separation conditions: instrument: GILSON 281; chromatographic column: CHIRALPAK IE20*250mm, 5 μm; mobile phase: n-hexane; ethanol (10 mM ammonia), flow rate: 20 mL/ min), the corresponding fractions were collected and concentrated under reduced pressure to give the title compounds 4-1 (25 mg, yield: 31.2%), 4-2 (25 mg, yield: 31.2%).

Single configuration compound 4-1 (shorter retention time):

MS m/z (ESI): 409.2 [M+1].

Chiral HPLC analysis: retention time 10.1 min, purity: 95% (column: CHIRALPAK IE20*250 mm, 5 μm); mobile phase: n-hexane; ethanol (10 mM ammonia), flow rate: 20 mL/min).

¹ H NMR (500MHz, DMSO-d ₆ ): δ 12.60(d,1H), 10.63(d,1H), 7.96(s,1H), 7.58(dd,1H), 7.18-7.02(m,3H) , 4.45-4.40(m, 1H), 3.06-3.00(m, 4H), 2.93-2.84(m, 3H), 2.02-1.96(m, 2H), 1.76-1.72(m, 1H).

Single configuration compound 4-2 (longer retention time):

MS m/z (ESI): 409.2 [M+1].

Chiral HPLC analysis: retention time 15.34 minutes, purity: 95% (chromatographic column: CHIRALPAK IE20*250 mm, 5 μm); mobile phase: n-hexane; ethanol (10 mM ammonia), flow rate: 20 mL/min).

¹ H NMR (500MHz, DMSO-d ₆ ): δ 12.60-12.58(d,1H), 10.64-10.60(d,1H), 7.96(s,1H), 7.59-7.57(dd,1H), 7.18- 7.01(m, 3H), 4.48-4.40(m, 1H), 3.03-3.00(m, 4H), 2.93-2.84(m, 3H), 1.98-1.96(m, 2H), 1.72-1.67(m, 1H ).

Biological evaluation

Test example 1. HPK1 enzyme activity detection (ADP-Glo method)

1. Reagents and instruments

1) ADP-Glo Kinase Assay Kit (including ADP-Glo Reagent and Kinase DetectionReagent)

(Promega, V9101)

2) 1M Tris-HCl buffer pH=7.5 (Solebo, T1140)

3) 1M _MgCl2 (Invitrogen, AM9530G)

4) 1M DTT (Thermofisher, P2325)

5) 20mg/mL Bovine Serum Albumin (BSA) (TAKARA 2320)

6) ATP solution (10mM) (Thermofisher PV3227)

7) Dephosphorylated MBP (Sigma, 13-110) (hereinafter referred to as MBP)

8) HPK1 (Signalchem, M23-11G)

9) 96-well low volume white plate (Cisbio, 66PL96100)

10) PHERA star microplate reader (BMG labtech)

2. Experimental method

2.1 Reagent preparation

a.assay buffer: 40 mM Tris-HCl buffer, 7.5; 20 mM MgCl ₂ ; 0.1 mg/mL BSA; 50 μM

DTT;

b. HPK1 enzyme solution: prepare HPK1 enzyme solution with a final concentration of 1.5ng/μL in assay buffer;

c. Mixed substrates of ATP and MBP: prepare ATP with a final concentration of 60 μM and MBP with a final concentration of 0.6 ug/μL in the assay buffer, and mix the prepared ATP and MBP in equal volumes;

d. Compound: initial concentration 33.3 μM, 3-fold dilution, 9 concentration gradients. Assay for all concentrations of compounds

The buffer was diluted 33.3 times and used for later use.

2.2 Experimental steps

a. In a 96-well plate, add 2 μL of the prepared HPK1 enzyme solution to each well, and add 2 μL of assaybuffer without enzyme in the first column.

b. Add 2 μL of compound to each well, the first and last columns do not add compound, add DMSO as a control, centrifuge, mix and shake for 2 minutes, and incubate at room temperature for 10 minutes.

c. Add 2 μL of ATP and MBP mixed substrate to each well, centrifuge, mix and shake for 2 minutes, and incubate at room temperature for 60 minutes.

d. Add 6 μL of ADP-Glo Reagent to each well, centrifuge, mix and shake for 2 minutes, and incubate at room temperature for 40 minutes.

e. Add 12 μL of Kinase Detection Reagent (Kinase Detection Reagent) to each well, centrifuge, mix and shake for 2 minutes, and incubate at room temperature for 40 minutes.

f. Read the plate with a microplate reader and record the RLU (Relative luminescence unit) value.

g. Graphpad software was used to make graphs, and IC ₅₀ values of the compounds were calculated, as shown in Table 1.

Table 1 IC ₅₀ values of the compounds in the present disclosure for the inhibition of HPK1 enzymatic activity

Example number HPK1/IC₅₀(nM) 1 0.5 1-1 0.4 1-2 0.6 2 0.7 3-1 2.4 3-2 10.5 4 1.0 4-2 1.1

Conclusion: The disclosed compounds have obvious inhibitory effect on the activity of HPK1 enzyme.

Test Example 2. Detection of SLP76 protein phosphorylation in Jurkat cells (HTRF method)

1. Reagents and instruments

1) RPMI 1640 medium (Gibco, 61870044)

2) Fetal Bovine Serum (Gibco, 10099141C) (hereinafter referred to as FBS)

3) 75cm ² filter cap cell culture flask (Corning, 430641)

4) PBS, pH 7.4 (Gibco, 10010049)

5) CD3 Antibody, anti-human, pure-functional grade (Miltenyi Biotec, 130-093-387)

6) Phospho-SLP-76 (Ser376) cellular kit (Cisbio, 63ADK076PEG)

7) HTRF 96well low volume plate (Cisbio, 66PL96100)

8) 96-well plate (Corning, 3788)

9) Microplate shaker (Chilin Bell)

10) PHERA star microplate reader (BMG labtech)

11) Countstar BioMed automatic cell counter (Shanghai Ruiyu Biotechnology)

12) Ultra-clean workbench (Thermo, 1300ALL)

13) CO ₂ incubator (Thermo, I160)

2. Cells and culture methods

Jurkat E6-1 cells were purchased from the American Type Culture Collection Center (ATCC, TIB-152) and cultured in RPMI1640 medium (10% FBS). Cell culture density was maintained at 2 x 10 ⁵ to 2 x 10 ⁶ cells/mL, and passaged 2-3 times a week.

3. Compound Preparation

a. Test compounds were dissolved in DMSO to 5 mM.

b. Compound starting concentration 5mM, 3-fold dilution, 10 concentration gradients.

c. Dilute all concentrations of compounds by 100 times with culture medium and set aside.

4. Experimental steps

a. Jurkat cell count, adjust the cell density to 5×10 ⁶ /mL with fresh culture medium.

b. In a 96-well plate, 20 μL of cells were seeded in each well, and cultured at 37°C for 4 hours.

c. Add 5 μL of compound to each well (columns 1 and 12 add 5 μL of 0.5% DMSO) and incubate at 37°C for 1 hour.

d. Dilute CD3 antibody (CD3 Antibody) to 20ng/μL with culture medium, add 5 μL to each well (add 5 μL culture medium in column 1 as a control), and incubate at 37°C for half an hour.

e. Add 10 μL of lysis buffer to each well to lyse the cells, and shake at room temperature at 850 rpm for half an hour.

f. Take 16 μL of cell lysate into a new HTRF 96-well plate, add 4 μL of antibody mixture to each well, and place overnight at room temperature.

g. Read the plate with a microplate reader and record the signal values at 665nm and 620nm.

h. Graphpad software was used to draw the graph, and the IC ₅₀ value of the compound was calculated, as shown in Table 2.

Table 2 IC ₅₀ values of the compounds in the present disclosure for the inhibition of SLP76 protein phosphorylation in Jurkat cells

Example number SLP76 protein phosphorylation/IC₅₀(nM) 1 65 1-1 31 1-2 84 2 40 3-1 92.8 4 83.4 4-1 27.5 4-2 72

Conclusion: The disclosed compounds have obvious inhibitory effect on the phosphorylation of SLP76 protein in Jurkat cells.

Claims (19)

1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

ring a is selected from aryl, heterocyclyl and heteroaryl;

T ¹ is CR ^T1 Or a nitrogen atom;

G ³ and G ⁴ Are the same or different and are each independently CR ¹ Or a nitrogen atom;

G ⁸ is CR ^G8 Or a nitrogen atom;

G ¹ and G ² Are the same or different and are each independently selected from CR ² 、NR ³ Nitrogen atom, oxygen atom and sulfur atom;

G ⁵ and G ⁶ Are the same or different and are each independently selected from CR ⁴ R ⁵ 、NR ⁶ Oxygen atom and sulfur atom;

G ⁷ selected from the group consisting of CR ^G7a R ^G7b 、NR ^G7c Oxygen atom and sulfur atom;

G ⁹ selected from the group consisting of CR ^G9a R ^G9b 、NR ^G9c Oxygen atom and sulfur atom;

r is the same or different and is each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy and hydroxyalkyl; or

Two R together form oxo;

R ⁰ 、R ³ 、R ⁶ 、R ^G7c and R ^G9c Are the same or different and are each independently selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

R’、R ¹ 、R ^T1 、R ^G8 and R ² Are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, - (CH) ₂ ) _m NR ⁷ R ⁸ 、-OR ⁹ Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁴ 、R ⁵ 、R ^G7a 、R ^G7b 、R ^G9a and R ^G9b The same or different, and each is independently selected from the group consisting of hydrogen atoms, halogens, alkyls, alkenyls, alkynyls, alkoxys, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyls, alkenyls, alkynyls, alkoxys, cycloalkyls, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogens, alkyls, alkenyls, alkynyls, alkoxys, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; or

R ⁴ And R ⁵ 、R ^G7a And R ^G7b Or R ^G9a And R ^G9b Wherein a pair together form an oxo group;

R ⁷ and R ⁸ Are the same or different and are each independently selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups; or

R ⁷ And R ⁸ Together with the nitrogen atom to which it is attached, form a heterocyclyl optionally substituted with one or more of halo, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy and hydroxyalkyl;

R ⁹ selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

m is 0, 1,2,3 or 4;

q is 0, 1,2,3 or 4; and is

n is 0, 1,2,3, 4,5 or 6.

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein

Is composed of

T ³ Is CR ^T3 Or a nitrogen atom, T ⁵ 、T ⁶ And T ⁷ Are the same or different and are each independently CR ¹⁰ Or a nitrogen atom;

T ² and T ⁴ Are the same or different and are each independently selected from CR ¹¹ 、NR ¹² Nitrogen atom, oxygen atom and sulfur atom;

R ¹⁰ 、R ^T3 and R ¹¹ Are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, - (CH) ₂ ) _m NR ⁷ R ⁸ 、-OR ⁹ Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, whereinSaid alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ¹² selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

R ⁷ 、R ⁸ 、R ⁹ and m is as defined in claim 1.

3. The compound according to claim 1 or2, which is a compound represented by the general formula (II) or (III):

wherein:

T ¹ 、G ³ 、G ⁴ 、G ⁵ 、G ⁶ 、G ⁹ r, R', q and n are as defined in claim 1.

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein G ⁵ Is CR ⁴ R ⁵ Or an oxygen atom; and/or G ⁶ Is CR ⁴ R ⁵ Or an oxygen atom; preferably, G ⁵ And G ⁶ One of them is CR ⁴ R ⁵ And the other is an oxygen atom; r ⁴ And R ⁵ As defined in claim 1.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein G is ⁹ Is NR ^G9c ，R ^G9c Is a hydrogen atom or C _1-6 An alkyl group; preferably, G ⁹ Is NCH ₃ 。

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein G is ³ Is CR ¹ (ii) a And/or G ⁴ Is CR ¹ ；R ¹ As defined in claim 1.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein T ¹ Is CR ^T1 ；R ^T1 As defined in claim 1; preferably, T ¹ Is C-NH ₂ 。

8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R is the same or different and each is independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; preferably, R is a hydrogen atom.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R' are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, and C _1-6 An alkyl group; preferably, R' is a hydrogen atom or a halogen.

10. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein q is 0 or 1.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

12. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, which is a compound of:

13. a compound represented by the general formula (IA):

wherein: r ^w Is an alkyl group;

G ¹ to G ⁹ R and n are as defined in claim 1.

14. A compound selected from the following compounds:

15. a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, which comprises:

carrying out cyclization reaction on the compound of the general formula (IA) or salt thereof and the compound of the general formula (IB) or salt thereof to obtain the compound of the general formula (I) or pharmaceutically acceptable salt thereof;

wherein: r ^w Is an alkyl group;

T ¹ is C-NH ₂ ；

Ring A, R ⁰ 、R’、q、G ¹ To G ⁹ R and n are as defined in claim 1.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

17. Use of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, in the manufacture of a medicament for inhibiting HPK 1.

18. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, for the manufacture of a medicament for the treatment and/or prevention of cancer, autoimmune diseases, inflammatory diseases, infectious diseases, cardiovascular diseases, neurodegenerative diseases, diabetes and diseases or conditions of reproductive disorders.

19. The use of claim 18, wherein the disease or condition is selected from the group consisting of cancer, allergy, asthma, sepsis, hiv infection, hepatitis b virus infection, ischemia, atherosclerosis, stroke, and alzheimer's disease; the cancer is preferably selected from brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urinary tract cancer, bladder cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma, and glioblastoma; the uterine cancer is preferably endometrial cancer.